Benzenesulfonyl ureas having hypoglycemic activity

ABSTRACT

BENZENESULFONYL UREA COMPOUNDS THAT ARE EFFECTIVE AS ORAL ANTIDIABETIC AGENTS ARE DISCLOSED TO HAVE THE FORMULA   (4-(X-N(-X1)-CO-NH-Y-)PHENYL)-SO2-NH-CO-NH-R   WHEREIN R IS (A) ALKYL OR ALKENYL OF 3-6 CARBON ATOMS, (B) ENDOALKYLENE-CYCLOHEXYL, ENDOALKYLENE-CYCLOHEXENYL, ENDOALKYLENE-CYCLOHEXYLMETHYL OR ENDOALKYLENE-CYCLOHEXENYLMETHYL OF 1-2 ENDOALKYLENE CARBON ATOMS, (C) BENZYL, PHENYLETHYL, (D) CYCLOHEXYL METHYL, (E) LOWER ALKYL CYCLOHEXYL OR DIALKYL CYCLOHEXYL, METHYL CYCLOPENTYL, (F) CYCLOALKYL OF 5-8 CARBON ATOMS IN THE RING (G) CYCLOHEXENYL, CYCLOHEXENYL-METHYL, METHYLCYCLOHEXENYL, OR (H) NORTRICYCLYL,   X-N(-X1)-   IS INDOLINO OR TETRAHYDROQUINOLINO, AND Y IS ALKYLENE OF 1 TO 3 CARBON ATOMS.

United States Patent U.S. Cl. 260-326.11 Claims ABSTRACT OF THE DISCLOSURE Benzenesulfonyl urea compounds that are effective as oral antidiabetic agents are disclosed to have the formula (a) alkyl or alkenyl of 3-6 carbon atoms,

-(b) endoalkylene-cyclohexyl, endoalkylene-cyclohexenyl, endoalkylene-cyclohexylmethyl or endoalkylene-cyclohexenylmethyl of 1-2 endoalkylene carbon atoms,

(c) benzyl, phenylethyl,

(d) cyclohexyl methyl,

(e) lower alkyl cyclohexyl or dialkyl cyclohexyl,

methyl cyclopentyl,

(f) cycloalkyl of 5-8 carbon atoms in the ring (g) cyclohexenyl, cyclohexenyl-methyl, methylcyclohexenyl, or

(h) nortricyclyl,

is indolino or tetrahydroqninolino, and Y is alkylene of 1 to 3 carbon atoms.

This application is a division of application Ser. No. 799,534, filed Feb. 14, 1969, now U.S. Pat. No. 3,655,756, which in turn is a continuation-in-part of application Ser. No. 511,900, filed Dec. 6, 1965, now abandoned, and application Ser. No. 636,290, filed May 5, 1967, now abandoned.

The present invention provides benzenesulfonyl-ureas corresponding to the general formula as well as salts of said benzenesulfonyl-ureas, in the formula R stands for:

(a) alkyl or alkenyl of 3 to 6 carbon atoms,

(b) benzyl, phenylethyl,

(c) cyclohexylmethyl,

(d) andoalkylene-cyclohexyl, endoalkylene-cyclohexenyl, endoalkylene-cyclohexylmethyl or endoalkylene-cyclohexenylmethyl of 1-2 endoalkylene carbon atoms,

(e) lower alkylcyclohexyl, lower dialkylcyclohexyl, methyl cyclopentyl,

(f) cycloalkyl of 5 to 8 carbon atoms,

(g) cyclohexenyl, cyclohexenyl-methyl, methyl cyclohexenyl,

(h) norticyclyl,

Y represents a saturated hydrocarbon chain containing 1-3 carbon atoms, and

X, X, and N together are indolino or tetrahydroquinolino.

In the foregoing and the following definitions lower alkyl in every case stands for an alkyl group containing l-4 carbon atoms in straight or ramified chain.

According to the above-mentioned definitions it may represent, for instance, propyl, isopropyl, butyl isobutyl, sec. butyl, straight-chained or ramified amyl (pentyl) or hexyl as well as the radicals corresponding to said bydrocarbon radicals and containing an ethylenic double linkage such, for instance, as allyl or crotyl. Furthermore, there are appropriate as R benzyl, a-phenylethyl or 5- phenylethyl.

Within the scope of the invention there are particularly preferred compounds containing as R a cycloaliphatic hydrocarbon radical which may be substituted by alkyl or linked to the nitrogen atom by means of alkylene. Said radicals comprise, for instance, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methyl cyclopentyl, methylcyclohexyl, ethyl-cyclohexyl, propyl-, and isopropyl-cyclohexyl. The alkyl groups can be present in the cyclohexyl ring preferably in 4-position to the sulfonyl-urea substituent and may take there the cisas well as the trans-position. Furthermore, there are mentioned: Endomethylene-cyelohexyl (2,2,l-bicycloheptyl), endoethylene-cyclohexyl (2,2 2-bicycloocty1), endomethylencyclohexenyl, endoethylenecyclohexenyl, endomethylenecyclohexenylmethyl or endoethylene-cyclohexenylmethyl, endomethylene-cyclohexylmethyl, endoethylene-cyclohexylmethyl.

The grouping means for example, indolino, tetrahydroquinolino, furthermore groupings of the following formulae C Ha H CH:

CH3 All .1113

l E IIg Cl I lCH3 0 3 C H3 0CH3 C 113 C 113 C1130 U H3 0 O t -Q-r l A) 0 H3 0 2H5 CI'I2 (111 (I) 0 H3 @a" t- C2115 C 2H5 Y may represent, for example, a saturated hydrocarbon radical of 1-3 carbon atoms in straight chain or branched, such as:

-CH CH -CH(CH )CH CH CH(CH The mentioned benzenesulfonyl-ureas may be prepared according to various methods which are generally used for the preparation of compounds of this kind. Thus amines of the formula RNH or, if desired their salts can be reacted with benzenesulfonyl isocyanates, benzenesulfonyl carbamic acid esters, benzenesulfonyl thiolcarbamic acid esters, benzenesulfonyl-ureas, benzenesulfonyl-semicarbazides or benzenesulfonyl-semicarbazones which are substituted by the group NC ONH-Y or benzenesulfonamides substituted by the group NC O-NH-Y or their salts can be reacted with R-substituted isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas or corresponding benzenesulfonyl-ureas containing in the molecule unsaturated compounds can be hydrogenated and the products obtained can be treated with alkaline agents if salt formation is desired.

According to the nature of X, X and R, in some cases one or the other process, mentioned for the preparation of individual compounds according to the general formula, might be inappropriate. Such relatively rare cases can easily be realized by experts and it is not difficult to use successfully a method of synthesis other than that described.

The mentioned benzenesulfonyl-carbamic acid esters or the benzenesulfonyl thiolcarbamic acid esters may contain in the alcohol component an alkyl radical or an aryl radical or also a heterocyclic radical. Since this radical is split off in the reaction, its chemical constitution does not influence the nature of the final product and it may therefore be varied within wide limits.

The same applies to the R-substituted carbamic acid esters or the corresponding monothiol-carbamic acid esters.

As carbamic acid halides, the chlorides are particularly suitable.

The benzenesulfonyl-ureas to be used as starting substances in the process of the present invention may be unsubstituted at the side of the urea molecule opposite to the sulfonyl group or may be monoor, in particular, disubstituted. Since these substituents are split off in the reaction with amines, their nature may be varied Within wide limits. In addition to benZenesulfonyl-ureas carrying alkyl-, aryl-, acylor heterocyclic substituents, there may also be used bis-(benzene-sulfonyl)-ureas which may carry, at one of the nitrogen atoms, an additional substituent, for example, methyl. For example, bis-(benzenesulfonyl)- ureas or also N-benzenesulfonyl-N'-acyl-ureas may be treated with amines of the formula R NH and the salts obtained may be heated to elevated temperatures, in particular, those above C.

Furthermore, it is possible to start from ureas of the formula H NCO---NHR or from ureas which may carry, at the free nitrogen atom, one or preferably two substituents, and to react these with benzene sulfonamides carrying in 4-position the substituent As such starting compounds, there may be mentioned for example the corresponding N'-acetyl-, N'-nitro-, N-cycloheXyl-, N (4 methyl-cyclohexyl)-, N,N'-diphenyl- (wherein the two phenyl) radicals may also carry substituents or may be linked to each other directly or over a bridge member such as CH NH-, O or S); N'-methyl-N'-phenyl-, N,N-dicyclohexyl-ureas as well as R-substituted carbamoyl-imidazols or -triazols.

As regards the reaction conditions, the forms of realizing the processes may in general vary within wide limits and adapted to each individual case. For example, the reaction using solvents may be carried out at room temperature or at an elevated temperature.

The benzenesulfonyl-urea-derivatives, obtainable according to present invention are valuable new remedies which are distinguished by a strong and long lasting blood sugar lowering action. The blood sugar lowering action can be determined for example at rabbits by feeding them the products of the present invention in a dose of 10 milligrams/kilogram, and measuring over a prolonged period of time, according to the known method of Hagedorn- Jensen or with an autoanalyzer, the blood sugar level. Thus, it was found, that N-[4-(fl-indolino-carbonamidoethyl) -benzenesulfonyl] -N- (4-methylcyclohexyl -urea in a rabbit provokes a lowering of the blood sugar of 32%, which after 24 hours still amounts to 29% and after 48 hours still 13%. The N-[4- (fi-indolinocarbonamidoethyl)- benzenesulfonyl]-N'-cyclohexylurea causes under given test conditions even a lowering of the blood sugar of 38% which, after 24 hours still amounts to Furthermore, it has been found, that N-[4- (,8- N- methyl-N phenyl-ureido -ethyl)-benzenesulfonyl]-N'- (4-methyl-cyclohexyl)-urea in a rabbit provokes after 3 hours a lowering of the blood sugar of 30%, which after 24 hours still amounts to 49%. The N- [4-(fi- N-4-methyl-phenyl-N-methyl-ureido -ethyl -benzenesulfonyl] -N'- (4-methyl-cyclohexyl)-urea causes after 6 hours under given test conditions a lowering of the blood sugar of 32%, which after 24 hours still amounts to 27% and after 48 hours still The N- [4 (Ii- 2-chlorphenyl-N- methyl-ureido -ethy1) benzenesulfonyl]-N-cyclohexylurea likewise causes after 3 hours a lowering of the blood sugar of which after 24 hours still amounts to 39%.

Corresponding values have been found with other compounds of this class as shown by the following table:

Blood sugar lowering Compound: in rabbits (percent) 1 N-[4 ([3 indolino-carbonamidoethyl)-benzenesulfonyl]-N'-(4-me-thyl-cyclohexyl)-urea N-[4-(fi- N 4 methylphenyl-N-methyl-ureido -ethyl)-benzenesulfonyl]-N'-(4 methylcyclohexyl)-urea N-[4-( 8- N 3 methylphenyl-N-methyl-ureido -ethyl)-benzenesulfonyl]-N'-(4 methylcycloh'exyD-urea N-[4-(ii- N-4-methoxyphenyl N methyl-ureido -ethyl)-benzenesulfonyl] N' cyclohexyl-urea N-[4-(B- N 3 trifluoromethylphenyl-N-methyl-ureido -ethyl)-benzenesulfonyl] N (4- methylcyclohexyl)-urea N-[4-(5- N 3 methoxyphenyl-N-methyl-ureido -ethyl)-benzenesulfonyl] N (4-methyl-cyclohexyl)-urea N-[4-(fl- 2 chlorophenyl-N'-methyl-ureido ethyl) benzenesulfonyl] N cyclohexylurea 30 1 After oral application of 10 ing/kg.

In contrast to this, the N-(4-methyl-benzenesulfonyl)- N'-butyl-urea which has been known as antidiabetic for oral administration when used in doses of less than 25 milligrams/kilogram remains without effect.

The benzenesulfonyl-ureas described are preferably used for the manufacture of orally applicable preparations for the lowering of the blood sugar level in the treatment of diabetes mellitus and may be used as such or in the form of their physiologically tolerable salts or in the presence of substances which cause such salt formation. For the formation of salts, there may be used alkaline agents, such, for example, as alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal or alkaline earth metal, carbonates, or bicarbonates, furthermore, ammonia or physiologically compatible organic nitrogen bases such as ethanolamin, diand triethanolamin.

The pharmaceutical preparations are preferably in the form of tablets containing, in addition to the compounds of the invention, the usual adjuvants and carriers such as talc, starch lactose, tragacanth or magnesium stearate.

A pharamaceutical preparation containing one of the aforesaid benzenesulfonyl-urea as active substance, for example, a tablet or a powder, with or without the aforesaid carriers is advantageously brought into a suitable unit dosage form. The dose chosen should comply with the activity of the benzenesulfonyl-urea used and the desired eifect. Advantageously, the dosage per unit amounts to about 0.5 to 100 milligrams, preferably 2 to 10 milligrams, but considerably higher or lower dosage units may also be used, which, if desired, are divided or multiplied prior to their administration.

The following examples serve to illustrate the invention, but they are not intended to limit it thereto.

6 EXAMPLE 1 N- [4- fl-indolino-carbamidoethyl) -benzenesulfonyl] -N- cyclohexylurea 17.2 g. 4-[fl-indolinocarbamidoethyl) benzenesulfonamide (melting point l89-l91 C., prepared from 4-(flaminoethyl)-benzenesulfonamide and indolinocarboxylic acid chloride) are suspended in 200 ml. of acetone and dissolved in water with a solution of 2 g. of sodium hydroxide. To this solution 6.5 g. cyclohexylisocyanate are added dropwise while stirring at room temperature and stirring is continued for 2 hours. The mixture is then diluted with water, filtered, and the filtrate is acidified with dilute hydrochloric acid. The precipitating N-[4-(B- indolinocarbamidoethyl) benzenesulfonyl] N cyclohexyl-urea is reprecipitated from 1% of ammonia and recrystallized from water-ethanol. Melting point ZOO-202 C. In analogous manner there is obtained:

N-[4-(B-indolino-carbamidoethyl) benzenesulfonyl]-N'- 4-methylcyclohexyl)-urea, melting point 184l86 C., N- [4- fl-indolino-carb amidoethyl) benzenesulfonyl] -N- butyl-urea, melting point 193-195 C.,

N- 4- ,B-indolino-carb amidoethyl) benzenesulfonyl -N'- (4-ethylcyclohexyl)-urea, melting point l79-18l C., N- [4- ,B-indolino-carb amidoethyl) benzenesulfonyl] -N'- 2,S-endomethylene-cyclohexylmethyl) -urea melting point l74-176 C.

Furthermore it has been prepared in analogous manner:

N 4- 'y-indolinocarbonamidopropyl -benzenesulfony1] N'-cyclohexylurea, melting point C. (from methanol (water) from 4-(y-indolinocarbonamidopropyl)-benzensulfonamide (melting point 161 C.),

N-[4-(,G-indolino-caronamidopropyl)-benzenesulfonyl]- N-cyclohexylurea, melting point 174 C. (from methanol/ water), from 4-(B-indolinocarbonamidopropyl)-benzenesulfonamide melting point 171 C.,

N-[4-(fi l,2,3,4-tetrahydro-quinolino-carbamido ethyl) -benzenesulfonyl] -N-cyclohexyl-urea, melting point 184-186 C., from the 4-(;3- l,2,3,4- tetrahydro-quinolino-carbamido -ethyl)-benzene-sulfonamide, melting point 138-139 C.,

N-[4-(B l,2,3,4-tetrahydro-quinolino-carbamido ethyl)-benzene-sulfonyl]-N-buty1-urea, melting point 135-137 C.,

N-[4-(fl 1,2,3 ,4-tetrahydro-quinolino-carbamido ethyl)-benzene-sulfonyl]-N-(4-methyl-cyclohexyl)-urea, melting point 153-155 C.,

N-[4-(fl- N-benzyl-N-methy1-ureido ethyl)-benzenesulfonyl]-N-propyl-urea, melting point l42l44 C N- 4- ([3- N-benzyl-N-rnethyl-ureido ethyl) -benzene sulfonyl]-N'-hexyl-urea, melting point 98-101 C.,

N- [4- (fl- N-benzyl-N-methyl-ureido ethyl) -benzenesulfonyl]-N-benzyl-urea, melting point 157-l59 C N- [4- (5- N-benzyl-N-methyl-ureido ethyl) -benzene sulfonyl]-N-cyclohexylmethyl)-urea, melting point 167169 C.,

N-[4-(,3- N-benzyl-N-methyl-ureido ethyl)-benzenesulfonyl]N'-(A3-cyclohexenylmethyl)-urea, melting point -162 C.,

N- [4- fl- N-4-methoxyphenyl-N-methyl-ureido ethyl) benzenesulfonyl]-N'-(4-isopropyl-cyclohexyl)-urea, melting point 206-208 C.,

N- [4- (,3- N-4-ethoxy-phenyl-N-methyl-ureido -ethyl benzenesulfonyl]-N'-(4-tert.- utyl-cyclohexyl)- urea, melting point 154-156 C.,

N- [4- (B- N-3-methoxyphenyl-N-methyl-ureido ethyl)-benzenesulfonyl]-N'- (4-methyl-A3-cyclohexenyl)-urea, melting point 130-132 C.,

N-[4-(,8- N-4-chlorophenyl-N-methyl-uredio -ethyl)- benzenesulfonyl]-N'-(2,5-endomethylene-A3-cyclohexenyl)-urea, melting point 199-201 C.,

ureido -ethyl)-benzenesulfonamide, melting point 164-166 C.,

N- [4- ;8- N-4-tert. butylphenyl-N-methyl-ureido ethyl) -benzenesulfonyl] -N'-cyclohexyl-urea, melting point 191-193 C., from 4-(N-methyl-N-pheny1- ureido-methyl)-benzenesulfonarnide, melting point 156158 C.,

N- 4- N-methyl-N-phenyl-ureido-niethyl) -benzenesulfonyl]-N-(4-methyl-cyclohexyl)-urea, melting point 172-174" C. from 4-(fl- N-4-iodo-phenyl-N-methylureido -ethyl)-benzenesulfonamide, melting point 181183 C.,

N- [4- B- N-4-io do-phenyl-N-methyl-ureido -ethyl benzenesulfonyl]-N-(4-rnethyl-cyclohexyl) -urea, melting point 194196 C.

EXAMPLE 3 N- [4- (B- N-4-chlorophenyl-N-methyl-ureido ethyl)-benzenesulfonyl] -N'-cyclohexyl-urea 10.6 g. 4-(B- N-4-chlorophenyl-N-methyl-ureido ethyl)-benzenesulfonyl-methyl-urethane (melting point 188-190 C., prepared from 4-(,8- N-4 chlorophenyl-N- methyl-ureido -ethyl)-benzenesulfonamide and chloroformic acid methylester) are heated in an oil bath to 130 C. for 1 hour with 2.5 g. of cyclohexylamine. After cooling, the reaction product is precipitated from 1% of ammonia and recrystallized from Water/ ethanol. The N- [4-(,8- N-4-chloro-phenyl N methyl-ureido -ethyl)- benzenesulfonyl]-N'-cyclohexyl-urea melts at 173l75 C.

In analogous manner there is obtained: From 4-(B- N-4-methyl-phenyl-N-methyl-ureido -ethyl)- benzenesulfonylmethylurethane (melting point 166- 168 C., N-[4-(B- N-4-methyl-phenyl-N-methyl-ureido -ethyl)- benzenesulfonyl]-N-cyclohexyl-urea, melting point N- [4- B- N-4-methylphenyl-N-methylureido -ethyl benzenesulfonyl]-N'-cycloheptyl-urea, melting point 140142 C.,

N- 4- fl- N-4-methylphenyl-N-methyl-ureido -ethyl) benzenesulfonyl]-N-nortricylcyl-urea, melting point N-[4-(fi- N-4-rnethylphenyl-N-methyl-ureido ethyl)- benzenesulfonyl}-N-cyclopentyl-urea, melting point 156158 C.,

N-[4-(,8- N-5-chloro-Z-methoXy-phenyl-N-methyl- 12 ureido -ethyl) -benzenesulfonyl] -N'- 3,4-dirnethylcyclohexyD-urea, melting point 154156 C. We claim: 1. A compound of the formula (a) alkyl or alkenyl of 3-6 carbon atoms,

(b) endoalkylene-cyclohexyl, endoalkylene-cyclohexenyl, endoalkylene cyclohexylmethyl or endoalkylene-cyclohexenylmethyl of 1-2 endoalkylene carbon atoms,

(0) benzyl, phenylethyl,

(d) cyclohexyl methyl,

(e) lower alkyl cyclohexyl or lower dialkyl cyclohexyl, methyl cyclopentyl,

(f) cycloalkyl of 5-8 carbon atoms in the ring,

(g) cyclohexenyl, cyclohexenyl-methyl, methylcyclohexenyl, or

(h) nortricyclyl,

is indolino or tetrahydroquinolino, and Y is alkylene of l to 3 carbon atoms.

2. Compound of claim 11 wherein R is cyclohexyl or 4- methyl cyclohexyl.

3. Compound of claim 1 wherein Y is dimethylenet 4. N-[4-(fl-indolino carbonamido ethyl)-benzenesulfonyl]-N'-(4-methyl-cyclohexyl)-nrea.

5. N-[4-(fi indolinocarbonamidoethyl) benzenesulfonyl]-N'-cycloheXyl-urea.

References Cited UNITED STATES PATENTS 3,565,911 2/1971 Beregi et al 260-326.l1

ALEX MAZEL, Primary Examiner J. A. NARC-AVAGE, Assistant Examiner US. Cl. X.R. 260-287 R r im inn-W I PW W Liam i iiLi iii EL V15 MUi-R' LE' 14k; ii MUN Patent 5Jo99o8 Dated Januarv 9 197% Inventofls) Weber et al.

in the above-identified patent It is certified that error appears corrected as shown below: 9

and that said Letters Patent are hereby In the Heading:

After SerQ No, 78,984" insert --Claim Priority, applications Germany,

December 8,1964, F M 650 May 19 1966, F 49 207-- Signed and sealed this 29th day of May 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents :ORM powso (w'ss) uscoMM-Dc eos7s-pe9 v Q U.5. GOVERNMENT PRINTING OFFICE 2 I969 0-365-33,

Patent ZJOQQQOS Dated Januarv Q 1Q76 lnvent fl Weber et a1.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Heading:

After HSTD Noo 78 98 insert --Claim Priority applications Germany,

December 8 196% F ML 650 May 1A, 1966, F +9 207-- Signed and sealed this 29th day of May 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents FORM po'wso (10459) USCOMM-DC 60376-P69 U.5. GOVERNMENT PRINTING OFFICE I 1955 0-365-33. 

